Discovery May Aid Fight Against Cystic Fibrosis

“This work is important because pathogenic bacteria such as Pseudomonas aeruginosa (PA) use protein secretion systems to cause disease in their hosts,” said Joseph Mougous, lead author of the study conducted at Harvard Medical School (HMS). “In the case of PA, the host may be a cancer patient with a weakened immune system, a burn patient, or a person with cystic fibrosis (CF).” PA is a leading cause of cystic fibrosis patients' death. It is difficult to treat because it is resistant to many drugs.

Researchers at Argonne National Laboratory (ANL) provided one of the clues that contributed to the HMS discovery. Working through a number of pathogenic proteins, ANL protein crystallographer Marianne Cuff saw a bagel-shaped pore that might be involved in transferring toxins into cells. She deposited the structure of the protein, called Hcp1, into the Protein Data Bank, a resource used by biologists worldwide to find information about the proteins they are studying.

While exploring the Protein Data Bank, Mougous, who was studying PA in the laboratory of department chair John Mekalanos, recognised that the amino acid sequence of Hcp1 in PA closely resembled that of Hcp1 in Vibrio cholerae. The Mekalanos lab had previously discovered that the Hcp1 protein of V. cholerae is released from the bacterium via a novel secretion pathway. Because Hcp1 proteins from both pathogens belong to the same protein family, Mougous wondered whether the Pseudomonas Hcp1 might also be secreted via this pathway.

The Harvard and Argonne researchers quickly formed a collaboration and confirmed the hypothesis. They then turned their attention to Hcp1 in cystic fibrosis patients to gain more insight in the role of Hcp1 during infection. Working with cystic fibrosis patients at Children's Hospital Boston, the HMS researchers sought and found Hcp1 in the sputum of patients with P. aeruginosa. They also found Hcp1 antibodies in the patients' blood – further evidence that Hcp1 plays a critical role in the infection.